Formulated allergen preparation and its use

ABSTRACT

The invention is concerned with a formulated preparation to be used for oral administration and containing an immunotherapeutically active amount of at least one allergen. The characteristic feature of the invention is that said formulated preparation is resistant to gastric juice and contains an antiallergic substance.

The present invention is concerned with a novel formulated preparationcontaining an immunotherapeutically active amount of at least oneallergen. The invention comprises also a method of treating allergicconditions by oral administration of the formulated preparation.

Allergic disorders may arise when the body is exposed to foreignsubstances, for instance due to inhaling of such substances or due totheir contacting the skin or mucous membranes, or due to their reachingthe body via the food ingested. Hypersensitivity reactions may occur,resulting from stimulation of immunological or other mechanisms.

The term "allergen" is used here and subsequently to mean a substancewhich, when exposed to a mammal, will be able to mount an immuneresponse resulting in antibodies of the IgE-class and which also will beable to trigger an allergic reaction when the mammal later on is exposedto the substance. Allergens are chemically a very heterogenous class ofcompounds and they may consist of protein, a lipid, a carbohydrate or acombination thereof such as a glycoprotein, a proteoglucan, alipoprotein etc.

Some compounds eliciting allergenic activity have to combine withbiopolymers in vivo in order to mount the immune response or to triggerthe allergic reaction in question.

Among immunologically-based disorders, the most dramatic one is theso-called atopic or IgE mediated allergic reaction which in its mostsevere form may result in a so-called anaphylactic shock which ispotentially fatal. This disorder is characterized by the presence ofantibodies of the immunoglobulin E class (IgE) which are capable ofbinding just that foreign substance (allergen) to which the individualis hypersensitive. These IgE antibodies moreover have the property ofbinding to the surface of certain cell types in the body. One such celltype is the mast cell which is present abundantly in the skin and in themucosae of e.g. the nose, eyes, trachea and intestine.

When IgE antibody coated mast cells are exposed to the allergen that hadoriginally "raised" the antibody, the mast cells are stimulated torelease so-called mediators. All these mediators, for example histamine,SRS-A (leucotrienes), PAF (platelet activating factor) and a number ofchemotactic factors and enzymes, contribute to the typical allergicinflammation which is characterized by (i) an early phase startingimmediately with edema, contraction of smooth muscles and increasedsecretion, and (ii) a late phase with infiltration of phagocytic cells.

There are different ways of alleviating an allergic condition. Two ofthese are utilized in accordance with the present invention, viz.:

(1) Immunotherapy, also called hyposensitization, whereby the aforesaidstimulation of the mast cell may be prevented, probably due to acombined effect of developing immunological tolerance (inhibiting IgEantibody formation) and forming so-called blocking antibodies whichbelong to other classes of immunoglobulins.

(2) Pharmacotherapy, by which allergic symptoms may be averted ormitigated. Averting of the symptoms may be obtained by means of mediatorrelease inhibition (for instance by administration of antiallergicsubstances such as e.g. disodium cromoglycate (DSCG) or other substanceswhich applied locally are apt to decrease or prevent mediator formationor release, such as e.g. calcium antagonists, substances increasing theCAMP level or substances interfering with leucotriene synthesis).Mitigation of the symptoms may be obtained by inhibition of the effectof the mediators (for instance by administration of antihistamine or ofantagonists to other mediators or of substances having opposite effectssuch as e.g. adrenergics, anticholinergics or xanthine derivatives).

An antiallergic substance of the DSCG type is believed to locally affectthe mast cell so as to inhibit release of histamine and other mediatorsof the immediate allergic reaction. To be effective the drug has toreach the mast cell prior to the exposure to allergen. Ever since thediscovery of DSCG, attempts have been made to find other compoundsinhibiting this reaction. Ketotiphene, for instance, has been said to besuch a potential compound. But unfortunately, such potentially promisingsubstances are very rarely as effective in actual fact as they haveseemed to promise.

The term "antiallergic substance" is used here and subsequently to meana substance inhibiting the allergen-induced allergic and inflammatoryreaction. Consequently such "antiallergic substances" should beunderstood to comprise substances inhibiting mediator release as well assubstances neutralizing the mediators themselves.

Immunotherapy means that an allergy patient is treated with smallamounts of the allergen to which he is allergic, the purpose of thistreatment being that the patient is to build up a defense or tolerancein action the next time he is exposed to that particular allergen. Thusthe object is to prevent the allergen from binding to its specific IgEantibodies on the mast cell. In immunotherapy treatment, the patient isgiven repeated administrations of (immunotherapeutically active amountsof) allergen to thereby build up his defense. However, the doses mustnot be so high as to give rise to an allergic reaction. It willtherefore be appreciated that immunotherapy implies a precariousbalancing between the administration of an effective dose and theprevention of an anaphylactic reaction.

Immunotherapy is normally carried out by means of subcutaneousinjections of allergen. For certain food allergies it has, however, beensuggested that the normal route of the allergen should be utilized, thuscomprising oral administration and absorption in the stomach orintestine. It has been suggested also, in this context, that thehyposensitizing treatment should be combined with DSCG administration.

Thus in connection with food allergies oral hyposensitization combinedwith oral administration of DSCG has been previously known. The role ofDSCG was believed to reside in exerting its effect locally in thedigestive tract, i.e. in the zone where exposure to the allergen takesplace. Tests have been carried out in which food allergy patients havebeen given 180-300 mg of DSCG for 3-10 days before allergenic challenge(La Nouv. Presse Med. 8, (1979):22, p. 1851-52). These tests haveultimately resulted in a proposal for an oral hyposensitizing methodwhich is quite rudimentary and involves many disadvantages. Theteachings of the reference are conducive to a hyposensitizing method inwhich exposure to the allergen and ingestion of DSCG take place atentirely different times. This is unpractical because the digestivefunctions of the stomach and intestine are apt to vary from individualto individual and at different occasions in one individual. Moreover ithas been found to be difficult, with concomitant risks, to persuadeparticipant indidividuals to repeatedly ingest two differentpreparations at different occasions; it should be noted here thatdeviations from a strict dose administration schedule entrain the riskof an anaphylactic reaction. The obstacles of the prior art methods fororal and/or intestinal hyposensitization are mainly the same as for skinhyposensitization. Even in a very weak allergy there is always a riskfor an anaphylactic reaction. Once adverse reactions have been initiatedtheir further development is hard to control.

Capsules containing allergen and intended for oral administration havealso been described by Stickl, H. and by Stickl. H. conjointly withKersher, G. (Fortschr. Med. 99 (1981), p. 1991-3, and 16th 98 (1980), p.343-46, respectively). However, unpublished results (Bjorksten, B.) haveshown that oral administration of allergen capsules may give rise toside effects in the form of diarrheas and other unpleasant phenomena.The work of both Bjorksten and Stickl has been directed towardsimmunotherapy irrespective of whether or not the allergen is afoodstuff.

Earlier on, attempts have been made also with so-called peroralhyposensitization. According to this method dilute solutions of theallergen have been placed under the patient's tongue. The method hasbeen found to be virtually ineffective.

From what has been said above it will be evident that there is a greatneed of novel formulated preparations and improved methods fornon-parenteral hyposensitization. Such preparations and such methods areprovided by the present invention which is aimed at eliminating theaforesaid disadvantages inherent in the earlier methods andpreparations. The greatest advantage provided by the invention is thatthe immunotherapeutic dose can now be increased considerably without anysignificant increase of the risk of provoking an anaphylactic reaction.The present invention will enable, for intestinal hyposensitizationpurposes, to administer the correct dose of the allergen preceded by aprotective dose of an antiallergic substance at the correct locationwith a predetermined time lag between delivery of the protectivecompound and the allergen.

The formulated preparation according to the invention is characterizedby being resistant to gastric juice and containing a therapeuticallyactive amount of an antiallergic substance. The preparation is intendedfor oral administration, and in a preferred embodiment is characterizedin that upon being administered it gives a delayed release of both theactive amount of the antiallergic substance and theimmunotherapeutically active amount of the allergen so that both ofthese are released, in the order as stated, when exposed to the actionof intestinal juice while remaining unreleased under the action ofgastric juice. By "resistant to gastric juice" is meant that thepreparation resists attack by gastric juice, so that a therapeuticallyactive amount of both the allergen and the antiallergic substance canpass through the stomach and be released in the intestine. The conceptof "resistance to gastric juice" is widely known and accepted, and thisterm has been in use for almost a century.

The invention also comprises a method for intestinal immunotherapytreatment of allergies, in the first place IgE mediated allergies.According to this method a formulated preparation of the type as setforth above is administered orally to a patient who is allergic to theallergen in said preparation. The invention is in particular concernedwith a method, and a preparation formulated therefore, which duringintestinal immunotherapy will inhibit the allergic reaction, especiallythe immediate allergic reaction.

The term "intestinal immunotherapy" means that the treatment is carriedout by causing the allergenic material to be delivered to and absorbedin the intestine. This type of hyposensitization is not restricted tothe case where the allergen is one that is present in a foodstuff: alsoother allergens may be employed.

The most important allergens to be used according to the invention arethe so-called food allergens and inhalation allergens. This types ofallergens are of proteinaceous nature having more than one antigenicdeterminant and a molecular weight of more than 2000 daltons, either initself or combined with body proteins. Examples of low molecular weightallergens are drugs, such as penicillin, and reactive chemicals. Theproteinaceous allergens are mostly used in the form of extracts, whichare derived from their natural sources. Common proteinaceous allergensare found in dust, mites, plants, animals, fungi, insects and insectvenoms, food etc.

In the light of experience made to date, the most preferred antiallergicsubstance to be employed according to this invention is of the typewhich inhibits mediator release. Examples are disodium cromoglycate,homologues and analogues thereof, and other therapeutically active andpharmaceutically acceptable salts, esters or amides of the correspondingacids. The invention also covers substances which will be found later onto have the same effect as DSCG ("DSCG effect"); compounds of theDSCG-type are described in U.S. Pat. No. 3,419,578. They are calledBis-Chromonyl compounds and have the general structure: ##STR1## whereinR₁, R₂, R₃, R₄, R₅ and R₆ are the same or different and each is H orhalogen, lower alkyl, hydroxy, lower alkoxy, substituted lower alkyl orsubstituted lower alkoxy, and X is a saturated or unsaturated,substituted or unsubstituted, straight or branched polymethylene chainwhich may be interrupted by one or more carbocyclic rings oroxygen-containing heterocyclic rings, oxygen atoms or carbonyl groups.

The advantages of the invention are in the first place derived from thefact that (i) the allergen and (ii) the antiallergic substance areadministered in the form of one formulated preparation in which both (i)and (ii) are present. The invention enables a therapeutically activeamount of the antiallergic substance to be administered locally to theintestine. Local release of a therapeutically active amount of theantiallergic substance takes place within a well-defined period of timebefore the allergen becomes available for producing an anaphylacticresponse.

The formulated preparation according to the present invention enablesantiallergic substance to be relased as soon as it has reached theintestine; but also earlier. In this latter case, however, it isimperative that a therapeutically active amount of the substance stillremains in the formulated drug preparation so that it can be releasedtherefrom when the preparation reaches the intestine. Normally theantiallergic substance or most of it should be released within 60minutes after arrival of the formulated preparation in the intestine,and most preferably within 30 minutes.

Allergen should not be released from the preparation before the latterhas reached the intestine. The allergen release in the intestine maythen start when an active amount of the antiallergic substance has beenreleased and become effective. In actual practice the allergen should bereleased within 120 minutes after arrival of the preparation in theintestine, preferably within 30 minutes after the bulk of theantiallergic substance has been released from the preparation in theintestine. The dissolution rate is defined by the conditions prescribedfor simulated intestinal juice in the US Pharamcopoea XX, p. 1105, andits third supplement p. 310-11.

For each dosage unit of the formulated preparation, the total amount ofallergen and the total amount of antiallergic substance may vary. Thesame applies to their proportions inter se. A substance having a lowantiallergic effect can be combined with only small amounts of allergen.Highly potent allergens will require larger amounts of antiallergicsubstance. DSCG is regarded as being non-toxic in itself and so may beadministered in unlimited amounts. Other substances exhibiting anantiallergic effect may give rise to side reactions, and consequentlyeach dosage unit may contain only small amounts of these activesubstances. It is important, however, that the amount of antiallergicsubstance per unit dose is always such in relation to the amount ofallergen per unit dose that it will inhibit any potential allergicreaction in the intestine. To an average person skilled in the art itwill be quite easy to ascertain the proper proportions and amounts thatare acceptable. A point to be noted here is of course that a patient maybecome sick if proportions are chosen wrongly.

As regards the volume of the dosage unit, its upper limit is set by thatwhich can be swallowed. As a rule this means that each unit will alwayscontain less than 500 mg of the antiallergic substance. The upper limitfor the amount of allergen is set by the ability of the antiallergicsubstance to protect the patient from an anaphylactic reaction; usuallythe amount of allergen per dosage unit is from 1 to 500 mg. Inimmunotherapy it is common practice to start with a low dose ofallergen. After this and as the treatment is proceeding further, it ispossible as a rule to increase the dose administered and consequentlythere may be a need of dosage units having different contents ofallergen. A further corollary is that even in a single individual theimmunotherapeutic amount for any given allergen may differ in differentstages of therapy. Of course the immunotherapeutic dose is affected alsoby purification and enrichment, as well as in some cases chemical orphysical modifications carried out for the purpose of increasing ordecreasing the allergenicity of the allergenic material.

When a plurality of different allergens are combined in a singleformulated preparation due attention must be paid to their relativepotencies and to such immunological cross reactivities as may sometimesoccur.

The preparations according to the invention may take various differentpharmaceutical forms. Examples of advantageous forms are double-wallcapsules, two-layer tablets and combinations thereof. Double-wallcapsules may contain the allergen in their interior (core capsule, core)and contain the antiallergically active substance in the space betweentheir walls (=in their envelope). Two-layer tablets may contain theanti-allergically active substance in their outer layer (=envelope) andcontain the allergen in their interior (=core). Capsule walls and/orlayer surfaces may advantageously be coated with a film resistant togastric juice or other film to thus become more resistant to gastricjuice attack or acquire more well-defined and predetermined releaseproperties. Coating of the core will cause a delay in the release of thecore contents. If a thicker coating is applied on the core the releaseof the allergen will be delayed still further in relation to the releaseof the antiallergic substance. Other types of preparations, too, may beused, such as for instance tablets containing microcapsules withallergens spread in and surrounded by the substance having anantiallergic activity. In its broadest concept the invention comprisesany and all forms for administration that give a delayed intestinalrelease of both the antiallergic substance and the allergen so thatimmunotherapy may proceed under the protection of the antiallergicsubstance.

The formulated preparation according to the invention may contain boththe allergen and the antiallergic substance together withpharmaceutically acceptable adjuvants, carriers and additives. All ofthese three types of additional ingredients are well-known to personsskilled in the art. The allergen is usually employed as an extract in afreeze-dried form.

Capsules and tablets which are resistant to gastric juice and havepredetermined release properties in intestinal juice may be producedaccording to known techniques ("The Theory and Practice of IndustrialPharmacy", Lachman L., Lieberman H. A. and Klanig J. L., 2nd edition LeaF. Febiger, Philadelphia, USA (1976), p. 321-465). Capsules of suitablesizes are commercially available. They are usually composed of gelatinor other material that will be unaggressive in the digestive tract.Filled capsules and compressed tablets are rendered resistant to gastricjuice by being coated with a film of resistant material. The material ofthe envelope or shell of the capsule will be a further factorcontributing to determining the rate of dissolution. One may thuschoose, for example, a gelatin dissolving at the pH of the intestinaljuice while remaining undissolved at the pH of the gastric juice. Inthat case there will be less need to apply a coating of a film which isresistant to gastric juice. In cases where a coating is applied thiswill be done with the coating material dissolved in a volatile solvent.Materials that are resistant to gastric juice are commercially availablefrom a multitude of commercial sources. Such materials may consist ofe.g. non-toxic cellulose esters and synthetic polymers. The materialsthat are useful in the context of the present invention are capable ofdissolving in intestinal juice having a pH higher than 3, preferablyhigher than 5, depending on where, i.e. in which intestinal region orzone, release is desired.

In the light of experience made to date, the most preferred modality ofthe invention is an enteric coated formulation containing aproteinaceous allergen in combination with the antiallergic substanceDSCG.

The invention is not in any way limited to the forms of administrationmentioned above, although capsules and tablets are currently beingregarded as having certain practical advantages. The below examples areset forth for the purpose of illustrating the invention and should notbe construed as limiting the scope thereof.

EXAMPLE 1 Double capsule resistant to gastric juice and containing anantiallergic substance as well as egg allergen Capsule

10 g of powdered egg albumen were subjected to briquetting, triturationand screening to 20 mesh, whereupon the thus resultant particles wereuniformly distributed into 100 gelatin capsules No. 5 (0.13 ml standardcapsule from Parke-Davis, USA). Each capsule was sealed and enclosedtogether with 100 mg disodium cromoglycate (DSCG) in a gelatin capsuleNo. 2 (0.37 ml standard capsule from Parke-Davis, USA). The outercapsules were then sealed and pan coated with a gastric juice resistantfilm material; this was applied in the form of a solution correspondingto that set forth in Example 4 (D).

Simulated gastric juice (US Pharmacopoea XX p. 1105 and its supplement 3p. 310-11) was employed for checking the gastric juice resistance of thedouble capsule obtained (2 h).

In an analogous manner, double capsules were produced in which the DSCGwas replaced by glucose.

Components dissolved out

The rate at which DSCG and egg albumen allergen were dissolved out wasmeasured in a bath of intestinal juice in accordance with USPharmacopoea XX p. 1105 and its supplement 3 p. 310-11, withdetermination of changes in protein concentration and in the lightabsorption of the bath at 325 nm (DSCG). Changes in proteinconcentration were determined according to the method of Bensadoun andWinstein, Analytical Biochemistry 70 (1976), p 241. The changes,expressed as a function of time, are set forth in Table 1a below:

                  TABLE 1a                                                        ______________________________________                                                    Release in intestinal juice, %                                    Time, min.    DSCG       allergen                                             ______________________________________                                         0             0          0                                                   15            10          2                                                   20            26          4                                                   25              33.5     11                                                   30            52         19                                                   35            78         29                                                   40            87         40                                                   50                       54                                                   60                       62                                                   80            100        78                                                   ______________________________________                                    

EXAMPLE 2

A series of double blind tests was run on egg hypersensitive patients toverify the proper performance of the preparation in vivo, that is, toverify that allergen can thus be supplied to the patients withoutcausing the local or general allergic reaction that would have followedupon traditional administration of a corresponding dose of the allergen.

The patients were given capsules produced according to Example 1. Thesewere either capsules containing egg albumen allergen together with DSCGor, respectively, capsules containing the egg albumen allergen buthaving the antiallergic agent replaced by glucose. The results are givenin Table 2. The preparation of Example 1 releases allergen at a timeinterval of 15 min. (average) after DSCG release.

                  TABLE 2                                                         ______________________________________                                               Clinical symptoms after administration of                                       Formulated preparation                                                                         Control preparation                                          (egg albumen     (egg albumen                                        Patient  allergen + DSCG) allergen + glucose)                                 ______________________________________                                        A        no reaction      vomiting                                                                      abdominal pain                                      B        no reaction      (not done)                                          ______________________________________                                    

It can be seen from these tests that by using combination capsulescontaining both the antiallergic substance and the allergen it ispossible to reduce the risk of anaphylactic reactions occurring in thecourse of intestinal immunotherapy.

EXAMPLE 3 Double capsules resistant to gastric juice and containingantiallergic substance as well as timothy grass pollen allergen

100 double capsules were produced in a manner similar to that ofExample 1. Each capsule contained an inner capsule with 10 mg pollen oftimothy grass (Phlemum pratense) and surrounded by 100 mg DSCG.

The antiallergic substance and allergen were dissolved out in a manneranalogous to Example 1. Also as in Example 1, DSCG was measured as thechange in final absorption at 325 nm. The changes occurring in theallergen activity of the bath (activity of timothy grass pollen) weremeasured by RAST inhibition, (Yman et al., Develop. biol. Stand. 29(1975), p. 151-165), as modified according to Schroder and Yman,(Allergy 35 (1980), p 234-236). It will be seen from Table 3 how theantiallergic and allergen substances were dissolved out successively.

                  TABLE 3                                                         ______________________________________                                        Release of DSCG and timothy grass                                             pollen allergen from double capsule                                                     Release in intestinal juice, %                                      Time, min.  DSCG    allergen, Phleum pratense                                 ______________________________________                                         0           0       0                                                        10           4       0                                                        20          21       2                                                        30          68      10                                                        40          89      40                                                        50                  60                                                        60          100     75                                                        ______________________________________                                    

EXAMPLE 4 Antiallergic Substance and Allergen in Double Tablet(Compressed Dragee) Resistant to Gastric Juice

Ingredients per tablet produced:

    ______________________________________                                                                 1 tablet                                             ______________________________________                                        A. Core                                                                       Powdered egg albumen (grade P:26 from                                                                    100    mg                                          Kallbergs Industri AB, Toreboda, Sweden)                                      Avicel ® (Ph 102, microcrystalline cellulose,                                                        18     mg                                          FML International, Cork, Ireland, see also                                    Merck Index 8th edition, Merck Co. Inc.,                                      Rahway, USA (1976) p. 246)                                                    Aerosil ® (silica particles, 2 nm, from                                                              1      mg                                          Degussa, Federal Republic of Germany)                                         Magnesium stearate         1      mg                                          B. Envelope                                                                   Disodium cromoglycate (DSCG)                                                                             100    mg                                          Avicel ®               98     mg                                          Aerosil ®              1      mg                                          Magnesium stearate         1      mg                                          C. Gastric juice resistant film, core                                         Eudragit ® L100 (esters of polymeth-                                                                 10     mg                                          acrylic acid, Rohm & Haas GmbH,                                               Darmstadt, Germany)                                                           *Ethanol 99.5%             73     mg                                          *Acetone                   73     mg                                          Citroflex 4 ® (softener, Pfizer, USA)                                                                6      mg                                          Propylene glycol           3      mg                                          D. Gastric juice resistant film,                                              compressed dragee                                                             Eudragit ® L100        30     mg                                          *Ethanol 99.5%             219    mg                                          *Acetone                   219    mg                                          Citroflex 4 ®          17     mg                                          Propylene glycol           9      mg                                          ______________________________________                                         evaporates and will not be present in the final product.                 

100 core tablets were prepared by introducing the item (A) materialsinto a mixer and mixing them homogeneously. Brilliant Blue was added asa marker to permit observation of allergen release from the tablet. Themixture was then compressed to tablets, and these were pan coated with asolution according to (C) above, whereby they were coated with a gastricjuice resistant film.

The materials according to item (B) were introduced into a mixer andmixed homogeneously. Then the core tablet as produced beforehand wascoated with an envelope of this mixture, the coating procedure beingperformed in a known per se manner by means of so-called compressioncoating. The resulting envelope was then pan coated with the solutionaccording to item (D) to thus form an outer film that was resistant togastric juice.

The tablets were shown to be gastric juice resistant, and the manner inwhich the substances were dissolved out was studied. All this was doneby means of techniques analogues to those of Examples 1 and 3. Theresults are set forth in Table 4.

                  TABLE 4                                                         ______________________________________                                        DSCG and allergen (Brilliant Blue) dissolved out from gastric                 juice resistant double tablet in intestinal juice at 37° C.                         % dissolved out                                                                         allergen measured                                      Time, minutes  DSCG    as Brilliant Blue                                      ______________________________________                                         5              9      --                                                     10             52      --                                                     15             75      --                                                     20             90      12                                                     30             101     93                                                     40             --      97                                                     ______________________________________                                    

I claim:
 1. A formulated preparation for oral administration andingestion containing an immunotherapeutically active amount of at leastone allergen, which preparation(i) is resistant to gastric juice andcontains in addition to said at least one allergen a therapeuticallyactive amount of an anti-allergic substance that will inhibit anallergen induced IgE-mediated allergic and inflammatory reaction, (ii)being composed of at least one inner core containing the allergen and ofan outer envelope which surrounds and confines said at least one coreand which contains said anti-allergic substance, and (iii) beingformulated so that upon being administed it gives a delayed release ofboth said active amount of antiallergic substance and saidimmunotherapeutic amount of allergen in a manner such that said twoamounts are released in the said order under the action of intestinaljuice, but not under the action of gastric juice, said allergen beingallergenic in the sense that it is able to mount an immune response in amammal resulting in antibody of the IgE-class and that it is able totrigger an allergic reaction when the mammal is later exposed to theallergen.
 2. A preparation according to claim 1 in which said envelopeis coated with a gastric juice resistant film.
 3. A preparationaccording to claim 1 in which each core is coated with a gastric juiceresistant film.
 4. A preparation according to claim 1 in the form of acapsule or tablet.
 5. A preparation according to claim 1 in which saidanti-allergic substance is an inhibitor for mediator release.
 6. Apreparation according to claim 2 in which said anti-allergic substanceis an inhibitor for mediator release.
 7. A preparation according toclaim 3 in which said anti-allergic substance is an inhibitor formediator release.
 8. A preparation according to claim 1 from which saidactive amount of anti-allergic substance and said immunotherapeuticamount of allergen are released within 60 and 120 minutes, respectively,under the action of intestinal juice.
 9. A preparation according toclaim 4 in which said allergic substance is a bis-chromonyl compound.10. A method for intestinal immunotherapy treatment of IgE mediatedallergy which comprises orally administering an immunotherapeutic amountof at least one allergen, characterized by administering a formulatedpreparation which is(i) resistant to gastric juice and contains inaddition to said at least one allergen a therapeutically active amountof an anti-allergic substance that will inhibit an allergen inducedIgE-mediated allergic and inflammatory reaction, (ii) composed of atleast one inner core containing the allergen and of an outer envelopewhich surrounds and confines said at least one core and contains saidanti-allergic substance, and (iii) formulated so that upon beingadministered it gives a delayed release of both said active amount ofanti-allergic substance and said immunotherapeutic amount of allergen ina manner such that said two amounts are released in the said order underthe action of intestinal juice, but not under the action of gastricjuice, said allergen being allergenic in the sense that it is able tomount an immune response in a mammal resulting in antibody of theIgE-class and that it is able to trigger an allergic reaction when themammal is later exposed to the allergen.